Dr. Gideon Koren, Professor of Medicine, is interested in understanding the pathogenesis of cardiac arrhythmias through three main lines of investigation: 1) Genomic studies to elucidate the transcriptional program(s) that control the expression of membrane polypeptides involved in determining the duration of cardiac action potential and early and late afterdepolarizations, as well as the aging of the heart. As part of these studies Dr. Koren is interested in studying the differentiation and senescence of adult cardiac stem cells; 2) Investigation of the trafficking and localization of voltage-gated potassium channels in the cardiomyocytes; and 3) Creation of genetically modified animal models for studying sudden cardiac death. Dr. Koren's laboratory is also focusing on the molecular mechanisms underlying the trafficking post translational modifications and turnover of Kv1.5 and KV2.1 potassium channels in the heart and protein interactions between HERG and KCNQ1. His group is characterizing the macromolecular complex (channelosome) that modulates the localization and function of several delayed rectifier potassium channels in the heart. In addition, his laboratory has analyzed and compared the phenotype of two novel transgenic rabbit models of long QT syndrome 1and 2 (LQT1 and LQT2) using surface ECG; monitoring of alert, free-moving rabbits, programmed electrical stimulation (PES) of the right ventricle of anesthetized rabbits, and analyses of the biochemical and electrophysiological phenotype of rabbit cardiomyocytes derived from the epicardial, mid-myocardial, and endocardial layers of the left ventricle.
Click here to view a select listing of Dr. Koren's Peer-Reviewed Publications
Dr. Ulrike Mende, Associate Professor of Medicine, has a longstanding interest in myocardial signaling mechanisms that control cardiac growth and function under normal and pathophysiological conditions. Signal transduction via G protein-coupled receptors is one of the most important mechanisms of signal transfer across the plasma membrane in virtually all cells, including heart cells. Heterotrimeric GTP-binding proteins (G proteins) act as relay switches that are responsible for proper transduction of cell surface signals to specific ion channels and/or second messenger pathways inside the cell. G proteins themselves are under the control of Regulators of G protein Signaling (RGS proteins). Dr. Mende's laboratory uses gain- and loss-of-function approaches both in vitro (primary cultures of cardiac myocytes) and in vivo (genetically modified mouse models) to delineate the functional role of G proteins and RGS proteins in the heart and to investigate how derangement in G protein-mediated signaling leads to cardiac hypertrophy and failure. Gene expression and regulation are examined with molecular biological approaches. Signal transduction pathways are analyzed with biochemical assays that measure enzyme activities and second messenger levels. Physiological approaches are utilized to assess calcium transients and contractile function in single myocytes and the intact heart. The Mende Laboratory recently extended their investigations to cardiac fibroblasts, the other major cell type in the heart. To better understand the mechanisms of myocyte/fibroblast cross-regulation, Dr. Mende and her team have forged alliances with Bioengineering faculty at Brown University to develop a cell culture model, in which individual cell orientation and the contact areas between myocytes and fibroblasts can be controlled. A three-dimensional co-culture system is also being developed.
Dr. Bum-Rak Choi, Assistant Professor of Medicine, aims to understand mechanisms of initiation and maintenance of cardiac arrhythmias, specifically, how mutations in ion channels and/or abnormal calcium handling cause chaotic rhythm. Our current understanding of abnormal Ca2+ handling is limited to mostly single cell preparation and the exact mechanisms of initiation and maintenance of cardiac arrhythmias are not clearly understood. Dr. Choi developed a dual imaging system which allows simultaneous recordings of membrane potential (Vm) and Ca2+ from intact heart using fluorescence probes and high speed cameras. Using these tools, he investigates their relationship in various pathological conditions such as ischemia or reperfusion induced arrhythmias, atrial and ventricular fibrillation, as well as heart failure. In addition, he also focuses on neuronal mechanisms that trigger ventricular arrhythmias in transgenic animal model of long QT syndrome. This project includes recordings of action potentials and Ca2+ transients from novel innervated heart preparation with intact sympathetic and vagal nerves. Dr. Choi also investigates the conduction system including the structure of the AV node and the role of Purkinje fiber network in arrhythmogenesis.
Dr. Hitesh Jindal, Assistant Professor of Medicine, is interested in performing proteomic studies to explore the expression profile of native proteins in cardiomyocytes as well as in fibroblasts under different physiological and pathological conditions. Using transgenic rabbits with long QT phenotype, he will employ 2-Dimensional Fluorescence Difference Gel Electrophoresis (2-D DIGE), an ultra-sensitive method that labels protein samples prior to 2-D electrophoresis, enabling accurate analysis of differences in protein profile or abundance between samples.
Dr. Karim Roder, Instructor of Medicine, research Interests surrounds ubiquitination and the roles it plays in trafficking of membrane proteins. He is interested in the possible role of novel ubiquitin ligases in the rabbit heart regarding action potential duration (APD) and conduction velocity (CV). To address this, both in vitro and in vivo experimental approaches including proteomics, the use of a novel 2D cardiomyocyte model, optical mapping and gene transfer are being used. The outcome of this study might lead to novel pathway(s) regulating APD or CV and identify novel genes that are linked to the QT interval.
Dr. Frank W. Sellke, the Karlson and Karlson Professor and the Chief of Cardiothoracic Surgery at the Alpert Medical School of Brown University and Lifespan, is an accomplished clinician, educator and researcher in the cardiovascular field. His research focuses on microcirculation of the heart, lung and other organs as it relates to vasomotor regulation, permeability, collateral development, and inflammation during cardiac surgery. The role of therapeutic angiogenesis and cell therapy for the treatment of inoperable coronary disease is a main focus of his work. He has utilized several clinically relevant pig models of chronic ischemia in diabetes and hypercholesterolemia to examine alterations in cell signaling and growth of collateral vessel formation and myocardial function. He also has an active participation in the search for drugs that can decrease myocardial cell death after ischemia-reperfusion.
Dr. Cesario Bianchi, Assistant Professor (Research), has a broad and extensive training ranging from electron microscopy to large-scale gene expression profile and biomarkers discovery. His actual research aims to determine the mechanisms leading to diet-induced myocardial protection and vulnerability to acute myocardial infarction using cell and molecular biology approaches in a large animal model of acute myocardial ischemia-reperfusion injury. He is also characterizing blood biomarkers that would predict cognitive dysfunctions in patients subjected to cardiopulmonary bypass.
Dr. Dmitry Terentyev, Assistant Professor of Medicine, is interested in processes that regulate cardiac contractility under both normal conditions and during cardiac disease. On a beat-to-beat basis, contraction and relaxation of myocytes composing the heart follows cyclical increases and decreases of cytosolic calcium. Our research is concerned with the mechanisms that govern functional activity of protein components of intracellular calcium handling machinery. Changes in calcium handling are responsible for the disease-related changes in strength of contraction (heart failure) and regularity of electrical activity of the heart (arrhythmias). The goal of our studies is to provide an understanding of how calcium handling is controlled in normal myocytes and how changes in these processes result in development of malignant arrhythmias and heart failure. Gaining insights into mechanisms of heart failure and cardiac arrhythmias is critical for the development of novel efficient therapeutic strategies. Specifically we are interested in regulation of calcium handling by microRNAs (miRNAs). MiRNAs are a family of small, ~21-nucleotide long, nonprotein-coding RNAs that have emerged as key post-transcriptional regulators of gene expression and are thought to have an unparalleled therapeutic potential. In order to gain better understanding of mechanisms that regulate cardiomyocyte function we use confocal life-cell imaging combined with methods of cellular electrophysiology, biochemistry and molecular genetics.
